Animal models on pain emphasize that small afferent input leads to a facilitated state of hyperalgesia and allodynia. Parallel experimental models in humans have been developed using quantitative sensory testing (QST) and models using thermal pulses and subdermal capsaicin to evoke a state of hyperalgesia and allodynia. Preclinical studies have shown that these hyperpathic states in animals are mediated by a peripheral and spinal pharmacology distinct from that which mediates acute C fiber excitation. Several characteristics are noted: i) Acute high, but not low threshold afferent input is affected by mu, alpha 2 agonists, and NSAIDS; ii) A state is induced by small afferent input which is mediated in part by NMDA receptors; and iii) Injured nerves may induce a state mediated in part by spontaneous activity mediated by increased sodium channels. These observations suggest several hypotheses which reflect drug action in humans. 1) Mu, alpha 2 agonism, and NSAIDS will have little effect upon thermal and mechanical thresholds; will increase thermal and mechanical pain thresholds and, reduce secondary hyperalgesia induced by small afferent activation, whereas NMDA antagonism will have little effect upon acute thresholds, but will reduce the secondary hyperalgesia. 2) Sodium channel blockade will diminish the secondary hyperalgesia with minimum effect upon acute thresholds. Using QST for thermal and mechanical thresholds, the generation of a painful state with thermal pulses and intradermal capsaicin, and delivery of sodium channel blocker, mu opioid agonists, alpha-2-agonist, NSAIDS, NMDA antagonists, and some miscellaneous analgesic drugs by the oral and intravenous route, the hypotheses presented will be tested in humans. These experimental pain states are believed to reflect mechanisms underlying components of the post nerve injury pain state. Thus, based on hypotheses derived from our understanding of the pharmacology of afferent processing derived from preclinical work, this proposal seeks to define whether 1) certain receptor and channel mechanisms influence the experimental human pain models; and, 2) that certain clinical pain states are mediated by mechanisms which have a comparable pharmacology to experimental human pain models and the corresponding animal model. These studies will provide support for the premise that there is a correlation of mechanisms between experimental and clinical states and that the experimental models can predict clinical efficacy of agents in anomalous human pain states.